There is a pressing need for new anti-HIV drugs that are effective against strains of the virus resistant to current regimens. Panacos Pharmaceuticals is collaborating with Professor K.H. Lee of the University of North Carolina at Chapel Hill to discover such compounds by screening plant extracts for HIV inhibitors, then designing synthetic analogs with improved antiviral and solubility properties. Dimethyl succinyl betulinic acid (DSB) is one of the most promising HIV drug candidates discovered in this collaboration. DSB potently inhibits replication by primary HIV-1 isolates and has a novel mechanism of action compared with approved drugs. Importantly, DSB is orally bioavailable with a half life of several hours in rats. The goal of this Phase I project is to determine DSB's suitability for further development. Proposed studies include: Analyzing antiviral activity against drug resistant HIV-1 strains; Elucidating mechanism of action; Studying DSB's metabolism in different species using in vitro liver microsome assays; Initiating formulation development; and extending the in vivo disposition, pharmacokinetic and metabolism analyses with DSB. An analog of DSB, dimethyl succinyl dihydrobetulinic (DSD), will also be studied in the metabolism and in vivo experiments, to provide an alternative development candidate if required. PROPOSED COMMERCIAL APPLICATIONS: The results of this Phase I SBIR project will be used to determine DSB's suitability for progressing into formal pre-clinical safety studies and initial clinical testing during the Phase II grant period. DSB has a novel mechanism of action compared with approved HIV drugs and may offer considerable potential as a new drug candidate for use in combination therapy of HIV/AIDS.